ArticleNature communications2023
DNAJB6 mutants display toxic gain of function through unregulated interaction with Hsp70 chaperones.
Article in Nature communications, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 19 papers.
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Who cites it
19 citing papers in PubMed, 40 citations in OpenAlex.
- FBXL21 regulates diurnal proteostasis in skeletal muscle by targeting DNAJB6 and client proteins.EMBO reports · 2026Article
- Human Hsp70 paralogs display selective J-domain interactions tuning proteostasis under stress.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- Accurate interdomain contacts in a mixed folded protein from NMR-guided coarse-grained simulations.Physical chemistry chemical physics : PCCP · 2026Article
- The ALS-associated E425K mutation uncouples DNAJC7 from the Hsp70 chaperone cycle.The FEBS journal · 2026Article
- Stress-specific expression of HSPA and DNAJ chaperones regulated by NRF2/HSF1 in neurodegenerative conditions.Molecular and cellular biochemistry · 2026Article
- Mechanisms and regulation of the Hsp70 chaperone network.Nature reviews. Molecular cell biology · 2026Review
- Multiplex neurodegeneration proteotoxicity platform reveals DNAJB6 promotes non-toxic FUS condensate gelation and inhibits neurotoxicity.Nature communications · 2025Article
- Mechanisms of assembly and function of the Hsp70-Hsp40 chaperone machinery.Molecular cell · 2025Article
- DnaJB1 chaperone inhibits tau aggregation by recognizing its N-terminus.bioRxiv : the preprint server for biology · 2025Article
- Molecular genetics of J-domain protein-related chaperonopathies in skeletal muscle.Journal of human genetics · 2025Review
- A low-complexity linker as a driver of intra- and intermolecular interactions in DNAJB chaperones.Nature communications · 2025Article
- Scouring the human Hsp70 network uncovers diverse chaperone safeguards buffering TDP-43 toxicity.bioRxiv : the preprint server for biology · 2025Article
- Protein isoform-centric therapeutics: expanding targets and increasing specificity.Nature reviews. Drug discovery · 2024Review
- Dominantly inherited muscle disorders: understanding their complexity and exploring therapeutic approaches.Disease models & mechanisms · 2024Review
- Abnormally High Expression of DNAJB6 Accelerates Malignant Progression of Lung Adenocarcinoma.Biomedicines · 2024Article
- Factors affecting protein recovery during Hsp40 affinity profiling.Analytical and bioanalytical chemistry · 2024Article
- Mitochondrial abnormalities contribute to muscle weakness in a Dnajb6 deficient zebrafish model.Human molecular genetics · 2024Article
- Tertiary structure and conformational dynamics of the anti-amyloidogenic chaperone DNAJB6b at atomistic resolution.Nature communications · 2024Article
- Unique characteristics of the J-domain proximal regions of Hsp70 cochaperone Apj1 in prion propagation/elimination and its overlap with Sis1 function.Frontiers in molecular biosciences · 2024Article
Corrections and comments
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Authors and funding
5 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Molecular chaperones are essential cellular components that aid in protein folding and preventing the abnormal aggregation of disease-associated proteins. Mutations in one such chaperone, DNAJB6, were identified in patients with LGMDD1, a dominant autosomal disorder characterized by myofibrillar degeneration and accumulations of aggregated protein within myocytes. The molecular mechanisms through which such mutations cause this dysfunction, however, are not well understood. Here we employ a combination of solution NMR and biochemical assays to investigate the structural and functional changes in LGMDD1 mutants of DNAJB6. Surprisingly, we find that DNAJB6 disease mutants show no reduction in their aggregation-prevention activity in vitro, and instead differ structurally from the WT protein, affecting their interaction with Hsp70 chaperones. While WT DNAJB6 contains a helical element regulating its ability to bind and activate Hsp70, in LGMDD1 disease mutants this regulation is disrupted. These variants can thus recruit and hyperactivate Hsp70 chaperones in an unregulated manner, depleting Hsp70 levels in myocytes, and resulting in the disruption of proteostasis. Interfering with DNAJB6-Hsp70 binding, however, reverses the disease phenotype, suggesting future therapeutic avenues for LGMDD1.
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